More than 200,000 infants continue to become infected with HIV-1 annually, accounting for 1/8th of the worldwide HIV-1 transmission, despite infants representing <2% of the world's population. Although maternal antiretroviral (ARV) treatment can dramatically reduce MTCT, even the most potent regimens have been unable to eliminate transmission, and their impact is weakened by poor maternal adherence, access, and monitoring. Recently, the addition of a 3rd ARV during pregnancy reduced peripartum HIV-1 transmission to <0.5%, yet came at the expense of a higher prematurity and death rate in infants, underscoring the need for additional and safer strategies to eliminate pediatric HIV-1. Developing immunologic interventions to eliminate vertical HIV-1 transmission will require defining the protective properties of maternal HIV-1 Env-specific antibodies that are passively transferred to the infant prior to birth and via breastfeeding. We recently identified commonly-elicited maternal antibody responses that predict reduced risk of MTCT using samples from the Women and Infants Transmission Study (WITS, n = 248), a cohort of U.S. HIV-1-infected mother-infant pairs enrolled in the pre-ARV era: 1) IgG responses directed against the Env variable loop 3 (V3), 2) CD4 binding site-specific antibody responses, and 3) neutralization of clade-matched tier 1 HIV-1 variants. Potentially explaining the mechanism behind these identified maternal immune correlates, we demonstrated that maternal Env V3-specific monoclonal antibodies can neutralize concurrently circulating autologous virus variants, despite having no activity against heterologous tier 2, difficult-to-neutralize viruses. Thus, we hypothesize that autologous neutralization by commonly-elicited, non-broadly neutralizing antibodies, such as those directed against the V3 loop and CD4 binding site, are mechanistic immune correlates of protection against MTCT and can be elicited by maternal Env immunization. In this grant, we will probe autologous neutralization by commonly-elicited Abs as a mechanism of protection against MTCT, based on our identified correlates of MTCT risk. We will determine whether autologous neutralization sensitivity distinguishes infant transmitted variants from maternal non- transmitted variants (Aim 1), map the Env regions and amino acid residues that define the neutralization sensitivity of infant transmitted viruses (Aim 2), and determine whether autologous neutralization responses can be enhanced by heterologous Env immunization among HIV-infected pregnant women in a historical clinical trial (Aim 3). Our results will establish whether autologous neutralization is a mechanism of protection against MTCT and a response that can be elicited by vaccine strategies. This work will establish guiding principles for design and evaluation of HIV-1 immunization strategies that will be necessary to eliminate the pediatric HIV-1 epidemic.